EZH1 转录因子下调预示三阴性乳腺癌患者预后不良。
Downregulation of the enhancer of zeste homolog 1 transcriptional factor predicts poor prognosis of triple-negative breast cancer patients.
机构信息
Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Department of Breast Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China.
出版信息
PeerJ. 2022 Jul 12;10:e13708. doi: 10.7717/peerj.13708. eCollection 2022.
BACKGROUND
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer and lacks effective biomarkers. This study seeks to unravel the expression status and the prospective transcriptional mechanisms of EZH1/EZH2 in TNBC tissue samples. Moreover, another objective of this study is to reveal the prognostic molecular signatures for risk stratification in TNBC patients.
METHODS
To determine the expression status of EZH1/EZH2 in TNBC tissue samples, microarray analysis and immunohistochemistry were performed on in house breast cancer tissue samples. External mRNA expression matrices were used to verify its expression patterns. Furthermore, the prospective transcriptional mechanisms of EZH1/EZH2 in TNBC were explored by performing differential expression analysis, co-expression analysis, and chromatin immunoprecipitation sequencing analysis. Kaplan-Meier survival analysis and univariate Cox regression analysis were utilized to detect the prognostic molecular signatures in TNBC patients. Nomogram and time-dependent receiver operating characteristic curves were plotted to predict the risk stratification ability of the prognostic-signatures-based Cox model.
RESULTS
In-house TMAs (66 TNBC . 106 non-TNBC) and external gene microarrays, as well as RNA-seq datasets (1,135 TNBC . 6,198 non-TNBC) results, confirmed the downregulation of EZH1 at both the protein and mRNA levels (SMD = -0.59 [-0.80, -0.37]), as is opposite to that of EZH2 (SMD = 0.74 [0.40, 1.08]). The upregulated transcriptional target genes of EZH1 were significantly aggregated in the cell cycle pathway, where , , , and were determined as key transcriptional targets. Additionally, the downregulated transcriptional targets of EZH2 were enriched in response to the hormone, where ESR1 was identified as the hub gene. The six-signature-based prognostic model produced an impressive performance in this study, with a training AUC of 0.753, 0.981, and 0.977 at 3-, 5-, and 10-year survival probability, respectively.
CONCLUSION
EZH1 downregulation may be a key modulator in the progression of TNBC through negative transcriptional regulation by targeting , , , and .
背景
三阴性乳腺癌（TNBC）是乳腺癌最恶性的亚型，缺乏有效的生物标志物。本研究旨在揭示 EZH1/EZH2 在 TNBC 组织样本中的表达状态和潜在的转录机制。此外，本研究的另一个目的是揭示用于 TNBC 患者风险分层的预后分子特征。
方法
为了确定 EZH1/EZH2 在 TNBC 组织样本中的表达状态，对内部乳腺癌组织样本进行了微阵列分析和免疫组织化学分析。使用外部 mRNA 表达矩阵验证其表达模式。此外，通过进行差异表达分析、共表达分析和染色质免疫沉淀测序分析，探索了 EZH1/EZH2 在 TNBC 中的潜在转录机制。采用 Kaplan-Meier 生存分析和单因素 Cox 回归分析检测 TNBC 患者的预后分子特征。绘制列线图和时间依赖性接收器操作特征曲线，以预测基于预后标志物的 Cox 模型的风险分层能力。
结果
内部 TMAs（66 例 TNBC，106 例非 TNBC）和外部基因微阵列以及 RNA-seq 数据集（1135 例 TNBC，6198 例非 TNBC）的结果证实，EZH1 的蛋白和 mRNA 水平均下调（SMD=-0.59[-0.80，-0.37]），而 EZH2 的表达上调（SMD=0.74[0.40，1.08]）。EZH1 的上调转录靶基因在细胞周期途径中显著聚集，其中、、、和被确定为关键转录靶基因。此外，EZH2 的下调转录靶基因在激素反应中富集，其中 ESR1 被鉴定为枢纽基因。基于六个标志物的预后模型在本研究中表现出色，在 3 年、5 年和 10 年生存率的训练 AUC 分别为 0.753、0.981 和 0.977。
结论
EZH1 的下调可能是通过靶向、、、和负向转录调控，成为 TNBC 进展的关键调节剂。
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